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Learning Objectives• Describe the use of new antibacterial agents in clinical practice
• Describe the therapeutic potential of antibiotics currently in development
Assessment Questions1. Which of the following statements regarding new antibacterial agents is
true?A. Most are FDA approved to treat a broad range of infections
B. Recently approved antibiotics are likely to become first-line agents
C. Many have a novel mechanism of action
D. Most are reserved for infections caused by organisms that are resistant to existing antibiotics
2. The majority of antibiotics currently in development target which pathogen(s)?
A. Gram-positive organisms
B. Gram-negative ESKAPE pathogens
C. Drug-resistant Neisseria gonorrheae
D. Drug-resistant Clostridioides difficile
Recently Approved Antibiotics
2018 Approvals Plazomicin (Zemdri®)
Evracycline (Xerava®)
Sarecycline (Seysara®)
Omadacycline (Nuzyra®)
Rifamycin (Aemcolo®)
2019 Approvals Imipenem, cliastatin, relebactam (Recabrio®)
Pretomanid
Lefamulin (Xenleta®)
Cefiderocol (Fetroja®)
Plazomicin (Zemdri®)
Approved• June, 2019
Indications• Complicated urinary tract infections (cUTIs), including pyelonephritis, caused by:
E. coli, K. pneumoniae, P. mirabilis, Enterobacter cloacae
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://zemdri.com/
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Class• Aminoglycoside
Mechanism of Action• Inhibits bacterial protein synthesis by binding the bacterial 30S ribosomal
subunit
Resistance• Aminoglycoside resistance results from production of aminoglycoside modifying
enzymes (AMEs), alteration of ribosomal target, up-regulation of efflux pumps, and reduced permeability due to porin loss
• Plazomicin is not inhibited by most AMEs that affect other aminoglycosides
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Spectrum of Activity
• Broad activity against β-lactamase and AME-producing Enterobacteriaceae
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter Cloacae
• In vitro susceptibility with unknown clinical significance
Citrobacter spp.
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia stuartii
Serratia marcescens
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Dosing and Administration
Dose
• 15mg/kg q24h over 30 minutes
• Renal dose adjustment required
Duration
• 4 to 7 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Warnings and Precautions
• Nephrotoxicity
• Ototoxicity
• Neuromuscular Blockade
• Fetal Harm
• Hypersensitivity reactions
• Clostridioides difficile-associated diarrhea
• Development of Drug-Resistant Bacteria
Black Box Warnings
• Nephrotoxicity
• Ototoxicity Hearing loss, tinnitus, vertigo
• Neuromuscular blockade
• Fetal harm
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Adverse Reactions
• Decreased renal function (11%)
• Diarrhea (7%)
• Hypertension (7%)
• Nausea/Vomiting (4%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Use in specific populations
Pregnancy Use not recommended
No available data
Lactation
Insufficient data in humans
Present in lactating rats, systemic exposure ~ 0.04% maternal exposure
Geriatric Use
Higher rates of adverse reactions in patients ≥ 65 years 40% of patients in clinical trials were ≥ 65 years
17.2 % of patients in clinical trials were ≥ 75 years
Pediatric Use Safety and efficacy not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf
Plazomicin (Zemdri®)
Clinical Trial Data
Two comparator-controlled clinical trials in patients with cUTI, including pyelonephritis
Compared to Meropenem
Non-inferior
Composite cure at day 5 (88% vs. 91.4%)
Higher % of patients had microbiologic eradication at test-of-cure visit (81.7% vs. 70.1%)
Small sample size (n=609)
Utility in clinical practice
Limited by adverse effects and limited safety & efficacy data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Plazomicin (Zemdri®)
Eravacycline (Xerava®)
Approved• August, 2018
Indications
• Complicated intra-abdominal infections (cIAI)
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf.
Eravacycline (Xerava®)
Class
• Synthetic tetracycline (fluorocycline)
Mechanism of Action
• Inhibits bacterial protein synthesis by binding to the 30S ribosome and preventing the incorporation of amino acids to the elongating peptide chain
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Resistance• Intrinsic multi-drug-resistant (MDR) efflux and ribosomal modification
• C7 and C9 substitution allows activity against some tetracycline-specific resistance mechanisms
Efflux mediated by tet(A), tet(B), and tet(K)
Ribosomal protection encoded by tet(M) and tet(Q)
• In vitro efficacy against Entreobacteriaceae
ESBL producing
AmpC producing
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Spectrum of Activity
• Gram-positive bacteria Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus
• Gram-negative bacteria Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca
• Anaerobic Bacteria Clostridium perfringens
Bacteroides spp.
Parabacteroides distasonis
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Dosing and Administration
Dose
• 1mg/kg every 12h over 60 minutes
• Renal dose adjustment not required
• Hepatic dose adjustment in patients with severe hepatic impairment (Child Pugh C)
1mg/kg q12h on day 1
1mg/kg q24h beginning on day 2
Duration
• 4 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Warnings and Precautions
• Hypersensitivity reactions
• Tooth discoloration and enamel hypoplasia
• Inhibition of bone growth
• Clostridioides difficile - Associated Diarrhea
• Potential for microbial overgrowth
• Development of drug-resistant bacteria
Adverse Reactions
• Infusion reactions (7.7%)
• Nausea (6.5%)
• Vomiting (3.7%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Drug interactions
• Strong CYP3A4 inducers
Decrease exposure of eravacycline
• Anticoagulants
Eravacycline may depress plasma prothrombin activity
Decrease dose of anticoagulant recommended
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Use in specific populations
Pregnancy Avoid in 2nd and 3rd trimester
Discoloration of teeth
Inhibition of bone formation
Lactation Avoid during treatment and for 4 days after discontinuation
No human data available
Geriatric Use No difference in safety and efficacy
Pediatric Use No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Clinical Trial Data
Two comparator-controlled clinical trials in patients with cUTI, including pyelonephritis
• Study 1
Non-inferior to ertapenem
Clinical cure (86.8% vs. 87.6%)
• Study 2
Non-inferior to meropenem
Clinical cure (90.8% vs. 91.2%)
Utility in clinical practice
Marketed as an alternative to minimize carbapenem use
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Eravacycline (Xerava®)
Sarecycline (Seysara®)
Approved• August, 2018
Indications
• Non-nodular moderate to severe acne in patients 9 years of age and older
Limitations of use
Efficacy beyond 12 weeks not established
Safety beyond 12 months not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf.
Sarecycline (Seysara®)
Class• Tetracycline (fluorocycline)
Mechanism of Action• Mechanism for treating acne vulgaris is unknown
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Dosing and Administration
Dose
• Dosing based on body weight
33-54 kg 60 mg
55-84 kg 100mg
85-136 kg 150 mg
Duration
• 12 weeks, then reassess treatment
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Sarecycline (Seysara®)
Warnings and Precautions
• Hypersensitivity reactions
• Tooth discoloration and enamel hypoplasia
• Inhibition of bone growth
• Clostridioides difficile - Associated Diarrhea
• Central Nervous System Effects
• Intracranial Hypertension
• Photosensitivity
• Potential for microbial overgrowth
• Development of drug-resistant bacteria
Adverse Reactions
• Nausea (3.1%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Sarecycline (Seysara®)
Drug interactions
• P-gp Substrates
Sarecycline may increase concentrations of P-gp substrates
Dose reduction may be required
• Anticoagulants
Sarecycline may depress plasma prothrombin activity
Decrease dose of anticoagulant recommended
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Sarecycline (Seysara®)
Use in specific populations
Pregnancy Avoid in 2nd and 3rd trimester
Discoloration of teeth
Inhibition of bone formation
Lactation Avoid use in breastfeeding women
No human data available
Geriatric Use No safety or efficacy data available
Pediatric Use No safety or efficacy data available for patients < 9 years of age
Safe and effective for patients ≥ 9 years
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Sarecycline (Seysara®)
Clinical Trial Data
• Study 1 Superior to placebo
IGA success (21.9% vs. 10.5%)
% reduction (52.2% vs. 35.2%)
• Study 2 Superior to placebo
IGA success (22.6% vs. 15.3%)
% reduction (50.8% vs. 36.4%)
Utility in clinical practice
Narrow spectrum tetracycline (Cutibacterium acnes strains)
Reduces exposure to broad-spectrum antibiotics (doxycycline)
Anti-inflammatory properties
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Sarecycline (Seysara®)
Omadacycline (Nuzyra®)
Approved• August, 2018
Indications
• Community-acquired bacterial pneumonia (CABP)
• Acute bacterial skin and skin structure infections (ABSSSI)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf.
Omadacycline (Nuzyra®)
Class• Tetracycline (aminomethylcycline)
Mechanism of Action
• Inhibits bacterial protein synthesis by binding to the 30S ribosome and blocks protein synthesis
Resistance• Overcomes resistance by
Tetracycline resistance active efflux pumps (tetK and tetL)
Ribosomal protection proteins (tetM)
• Active against
Some S. aureus, S. pneumo and H. influenzae strains with macrolide resistance genes (erm A, erm B, ermC)
Some strains with ciprofloxacin resistance genes (gyrA and parC)
β-lactamase positive H. influenzae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Spectrum of Activity - CABP
• Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus (MSSA)
• Gram-negative bacteria
Haemophilus influenzae
Haemophilus parainfluenzae
• Other microorganisms
Chlamydophila pneumoniae
Legionella pneumophilia
Mycoplasma pneumoniae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
https://www.nuzyra.com/hcp/antimicrobial-activity
Omadacycline (Nuzyra®)
Spectrum of Activity - ABSSSI
• Gram-positive bacteria
Enterococcus faecalis
Staphylococcus aureus (MSSA and MRSA)
Staphylococcus lugdunensis
Streptococcus anginosus grp
Streptococcus intermedius
Streptococcus constellatus
Streptococcus pyogenes
• Gram-negative bacteria
Enterobacter cloacae
Klebsiella pneumoniae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
https://www.nuzyra.com/hcp/antimicrobial-activity
Omadacycline (Nuzyra®)
Dosing and Administration
Dose
• CABP Loading dose: 200mg IV over 60 minutes or 100mg IV over 30 minutes q12h x 2 doses
Maintenance dose: 100mg IV over 30 minutes daily or 300mg PO daily
• ABSSSI Loading dose: 200mg IV over 60 minutes or 100mg IV over 30 minutes q12h x 2 doses
Maintenance dose: 100mg IV over 30 minutes daily or 300mg PO dailyOr
Loading dose 450mg PO q24h x 2 doses
300mg PO daily
• Renal and hepatic dose adjustment not required
Duration
• 7 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Warnings and Precautions
• CABP - Increase risk of mortality compared to moxifloxacin (2% vs. 1%) Cause not established
• Tooth discoloration and enamel hypoplasia
• Inhibition of bone growth
• Hypersensitivity reactions
• Clostridioides difficile - Associated Diarrhea
• Intracranial Hypertension
• Photosensitivity
• Development of drug-resistant bacteria
Adverse Reactions
• Nausea (21.9%)
• Vomiting (11.4%)
• Infusion site reactions (4.1%)
• LFT elevation (3.7% - 4.1%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Drug interactions
• Anticoagulants
Omadacycline may depress plasma prothrombin activity
Decrease dose of anticoagulant recommended
• Antacids and Iron containing products
Absorption is impaired by aluminum, calcium, magnesium, iron
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Use in specific populations
Pregnancy Avoid in 2nd and 3rd trimester
Discoloration of teeth
Inhibition of bone formation
Limited data available
Lactation Avoid during treatment and for 4 days after discontinuation
No human data available
Geriatric Use Insufficient data
Lower clinical success rates in patients ≥ 65 years
Pediatric Use No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Clinical Trial Data - ABSSSI
Trial 1
IV for 3 days, with the option to transition to PO (omadacycline vs. linezolid)
Non-inferior to linezolid
Clinical success at early clinical response (84.8% vs. 85.5%)
Clinical response at post-therapy evaluation (87.3% vs. 82.2%)
Trial 2
PO omadacycline vs. PO linezolid
Non-inferior to linezolid
Clinical success at early clinical response (84.8% vs. 85.5%)
Clinical response at post-therapy evaluation (87.3% vs. 82.2%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Clinical Trial Data - CABP
IV for 3 days, with the option to transition to PO (omadacycline vs. moxifloxacin)
Non-inferior to moxifloxacin
Clinical success at early clinical response (81.1% vs. 82.7%)
Clinical response at post-therapy evaluation (87.6% vs. 85.1%)
Utility in clinical practice
Treats CAP caused by resistant S. pneumoniae
Broad spectrum - empiric monotherapy for ABSSSI
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Omadacycline (Nuzyra®)
Rifamycin (Aemcolo®)
Approved• November, 2018
Indications• Traveler’s diarrhea caused by noninvasive strains of E. coli in adults
Limitations of use• Not for use in patients with diarrhea complicated by fever or bloody stool
• Indicated for E. coli only
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf.
Rifamycin (Aemcolo®)
Class• Ansamycin
Mechanism of Action
• Blocks DNA transcription by inhibiting DNA-dependent RNA polymerase
Resistance• Point mutations in the RNA polymerase beta subunit associated withresistance
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Dosing and Administration
Dose
388mg (2 tablets) PO BID for 3 days
• Safety and efficacy in renal and hepatic impairment not studied
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Rifamycin (Aemcolo®)
Warnings and Precautions• Risk of persistent or worsening diarrhea complicated by fever and/or bloody stool
• Clostridioides difficile - Associated Diarrhea
• Development of drug-resistant bacteria
Adverse Reactions• Constipation (3.5%)
• Headache (3.3%)
Drug interactions• None studied
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Rifamycin (Aemcolo®)
Use in specific populations
Pregnancy
No human data available
No evidence of fetal harm in animal studies
Lactation
No human data available
Geriatric Use
Insufficient data
Minimal absorption, minimal difference in safety/efficacy expected
Pediatric Use
No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Rifamycin (Aemcolo®)
Clinical Trial Data
Rifamycin 388mg PO BID for 3 days
Time to last unformed stool
Superior to placebo (46h vs. 68h)
Clinical cure
Superior to placebo (80.4% vs. 56.9%)
Utility in clinical practice Alternative to fluoroquinolones for Traveler’s diarrhea
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Rifamycin (Aemcolo®)
Imipenem, cilastatin, relebactam (Recabrio®)
Approved
• July, 2019
Indications
• Complicated urinary tract infections (cUTI)
• Complicated intra-abdominal infections (cIAI)
• Hospital-acquired bacterial pneumonia (HABP)
• Ventilator-acquired bacterial pneumonia (VABP)
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086080/#:~:text=This%20review%20focuses%20on%20the,2019)%20are%20new%20therapeutic%20options.
Imipenem, cilastatin, relebactam (Recabrio®)
Class
• Carbapenem/β-lactamase inhibitor
Mechanism of Action
• Inhibits bacterial cell wall synthesis (Imipenem)
• β-lactamase inhibitor (relebactam)
Protects imipenem from degradation by β-lactamases SVH, TEM, CTX-M, Enterobacter cloacae P99, PDC, KPC
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf
Resistance• No cross-resistance with other classes of antibacterial drugs
Some isolates resistant to cephalosporins and carbapenems are susceptible to imipenem/cilastatin/relebactam
• β-lactam resistance mechanisms in gram-negative organisms:
β-lactamase production
Up-regulation of efflux pumps
Loss of outer membrane porins
• Resistant to most isolates containing metalo-beta-lactamases and oxacillinases with carbapenemase activity
• Resistant Enterobacteriaceae
MBL or oxacillinase producing
• Resistant Pseudomonas aeruginosa
MBL, KPC, PER, GES, VEB, PDC producing
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf
Imipenem, cilastatin, relebactam (Recabrio®)
Spectrum of Activity
• Aerobic gram-negative bacteria
Acinetobacter baumannii complex
Enterobacter cloacae complex
Escherichia coli
Haemophilus influenzae
Klebsiella spp.
Pseudomonas aeruginosa
Serratia marcescens
• Anaerobic Bacteria
Bacteroides spp.
Fusobacterium nucleatum
Parabacteroides distasonis
https://www.merckconnect.com/recarbrio/mechanism-of-action/?#AntimicrobialActivity
Imipenem, cilastatin, relebactam (Recabrio®)
Dosing and Administration
Dose
• 1.25g IV q6h over 3 hours
Imipenem 500mg, cilastatin 500mg, relebactam 250mg
Renal dose adjustment required
CrCl < 60 mL/min
Duration
• 4 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf
https://www.merckconnect.com/recarbrio/dosing-administration/
Imipenem, cilastatin, relebactam (Recabrio®)
Pharmacokinetics
Elimination
• Half-life of ~1hr
Metabolism
• Cilastatin inhibits metabolism of imipenem by dehydropeptidase in the kidneys
• Relebactam is minimally metabolized
Excretion
• Renal
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Imipenem, cilastatin, relebactam (Recabrio®)
Warnings and Precautions
• Hypersensitivity reactions
• Seizures and CNS reactions
• Increased seizure potential with Valproic Acid
• Clostridioides difficile–associated diarrhea (CDAD)
Adverse Reactions
• Diarrhea (6%)
• Nausea (6%)
• Headache (4%)
• Vomiting (3%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Imipenem, cilastatin, relebactam (Recabrio®)
Use in specific populations
Pregnancy
Embryonic loss observed in monkeys treated with imipenem/cilastatin
Fetal abnormalities in mice treated with relebactam
Insufficient human data
Lactation
Insufficient data in humans
Relebactam present in milk of lactating rats
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf
Imipenem, cilastatin, relebactam (Recabrio®)
Use in specific populations
Geriatric Use
No difference in safety and efficacy
31% of patients in clinical trials were ≥ 65 years
11.6 % of patients in clinical trials were ≥ 75 years
Pediatric Use
No data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Imipenem, cilastatin, relebactam (Recabrio®)
Clinical Trial Data – HABP/VABP
Trial 1
Imipenem/cilastatin/relebactam vs. Piperacillin/Tazobactam
Non-inferior to Piperacillin/Tazobacctam
All cause mortality at 28 days (15.9% vs. 21.3%)
Higher mortality in HABP alone (12.7% vs. 11.5%)
Lower mortality with VABP and ventilated HABP (19.7% vs. 30.9%)
Trial 2
Imipenem/cilastatin/relebactam vs. imipenem/cilastatin + colistin
Non-inferior
All-cause mortality (9.5% vs 30%)
Clinical response at day 28 (71.4% vs. 40%)
Small sample size (n=30)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Imipenem, cilastatin, relebactam (Recabrio®)
Clinical Trial Data – cUTI and cIAI
Two individual trials
Imipenem/cilastatin + placebo vs Imipenem/cilastatin/relebactam
Designed to identify side effects
Increased diarrhea, LFT elevation with Imipenem/cilastatin/relebactam
Utility in clinical practice
Reserved for MDR organisms
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Imipenem, cilastatin, relebactam (Recabrio®)
Cefiderocol (Fetroja®)
Approved
• November 11, 2019
Indications
• Complicated urinary tract infections (cUTI)
Reserved for use in patients ≥ 18 years of age with limited treatment options
• Hospital-acquired bacterial pneumonia
• Ventilator-associated bacterial pneumonia
https://www.fetroja.com/mechanism-of-action/
Cefiderocol (Fetroja®)
Class
• Siderophore cephalosporin
Mechanism of Action
• Inhibits bacterial cell wall synthesis
• Functions as a siderophore to gain access via the bacteria’s iron-transport system
Binds to extracellular free ferric iron
Evades resistance by overcoming porin channel alterations
https://www.fetroja.com/mechanism-of-action/
Cefiderocol (Fetroja®)
Resistance• No cross-resistance with other classes of antibacterial drugs
• Stable against all classes of β-lactamases
• Overcomes efflux pump up-regulation
https://www.fetroja.com/mechanism-of-action/
Cefiderocol (Fetroja®)
Spectrum of Activity
• Aerobic gram-negative bacilli
Acinetobacter baumannii complex
Escherichia coli
Enterobacter cloacae complex
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens
In vitro activity
Citrobacter freundii complex, Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca, Morganella morganii, Proetus vulgaris, Providencia rettgeri, Stenotrophomonas maltophilia
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Dosing and Administration
Dose
• 2g IV q8h over 3 hours
Renal dose adjustment required
CrCl < 60 mL/min
CrCl ≥ 120 mL/min
Duration
• 7 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Pharmacokinetics
Elimination
• Half-life of 2-3 hours
• Clearance ~ 5L/hr
Metabolism
• Minimal metabolism
Excretion
• Renal
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Warnings and Precautions
• Increase in all-cause mortality in patients with carbapenem-resistant gram-negative infections
• Hypersensitivity reactions
• Clostridioides difficile–associated diarrhea (CDAD)
• Seizures and other CNS reactions
• Development of Drug-Resistant bacteria
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)Adverse Reactions
• Diarrhea (4%)
• Infusion site reactions (4%)
• Constipation (3%)
• Rash (3%)
Drug/Laboratory Test Interactions
• False-positive dipstick tests Urine protein, ketones, occult blood
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Use in specific populations
Pregnancy
No data available
Cephalosporins typically safe for use in pregnancy
Lactation
No data in humans
Detected in milk of lactating rats (6% of peak plasma level)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Use in specific populations
Geriatric Use
No difference in safety and efficacy
Pediatric Use
No data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Lefamulin (Xenleta®)
Approved
• August, 2019
Indications
• Community Acquired Bacterial Pneumonia
Future Indications
• Acute Bacterial SSTI
Phase 2 trials complete
• Complicated UTI
Phase 1 trials initiated
Novel Antibiotics | Lefamulin | Nabriva.com.
Lefamulin (Xenleta®)
Class Pleuromutilin antibacterial agent
Mechanism of Action Inhibits bacterial protein synthesis through interaction with the A- and P- sites of the peptidyl
transferase of the 23S rRNA of the 50S subunit
Interacts via hydrogen bonds, hydrophobic interactions, and Van der Waals forces
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf
Resistance
• Modifications of the ribosomal target ABC-F proteins
Vga (A,B,E), Isa(E), sal (A), Cfr methyl transferase
Cfr methyltransferase can mediate cross-resistance between lefamulin and lincosamides, oxazolidinones, and streptogramins
• Mutation of ribosomal proteins L3 and L4
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Spectrum of Activity
Gram-positive Bacteria
Streptococcus pneumoniae
Staphylococcus aureus (MSSA)
Gram-negative Bacteria
Haemophilus influenzae
Other Bacteria
Mycoplasma pneumoniae
Chlamydophila pneumoniae
Legionella pneumophilia
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Potential Spectrum of Activity
Gram-positive Bacteria
Staphylococcus aureus (MRSA)
Streptococcus agalactiae
Streptococcus anginosus
Streptococcus mitis
Streptococcus pyogenes
Streptococcus salivarius
Gram-negative Bacteria
Haemophilus parainfluenzae
Moraxella catarrhalis
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Dosing and Administration
Dose
• 150mg IV q12h over 60 minutes
• 600mg PO q12h
Administer 1 hours before or 2 hours after meals
Duration
• 5-7 days
Dose adjustment
• Hepatic Impairment
150mg IV q24h over 60 minutes (Child-Pugh Class C)
Tablets not recommended with moderate or severe hepatic impairment (Child-Pugh Class B or C)
• Renal dose adjustment not required
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Pharmacokinetics
Absorption Decreased bioavailability when administered with food (PO)
Metabolism CYP3A4 metabolism
Elimination Elimination half-life ~ 8 hours
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Warnings and Precautions
• QT Prolongation
• Embryo-Fetal Toxicity
Verify pregnancy status before initiation
• Clostridioides difficile-associated diarrhea (CDAD)
• Development of drug resistant bacteria
Adverse Reactions
• Diarrhea (12%)
• Infusion site reaction (7%)
• Nausea (5%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Lefamulin (Xenleta®)
Drug Interactions
Strong CYP3A4 inducers/inhibitors
Strong P-gp inducers/inhibitors
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Lefamulin (Xenleta®)
Use in specific populations
Pregnancy
May cause fetal harm
Pregnancy pharmacovigilance program established for Xenleta
Lactation
No human data
Concentrated in mild of lactating rats
Recommend pumping and discarding milk during administration and for 2 days after discontinuation of lefamulin
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Use in specific populations
Geriatric Use
No difference in safety and efficacy
41.5% of patients in clinical trials were ≥ 65 years
Pediatric Use
Safety and efficacy not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Clinical Trial Data
Two multicenter, multinational, double-blind, double-dummy, non-inferiority trials
• Trial 1
Lefamulin (5-10 days) compared to Moxifloxacin ± Linezolid (7-10 days)
IV administration of all antibiotics for at least 3 days before transition to PO
Non-inferior to Moxifloxacin ± Linezolid
Early Clinical Response 87.3% vs. 90.2%
Clinical Response at Test of Cure 80.8% vs. 83.6%
• Trial 2
PO Lefamulin (5 days) compared to PO Moxifloxacin (7 days)
Non-inferior to Moxifloxacin ± Linezolid
Early Clinical Response 90.2% vs. 90.2%
Clinical Response at Test of Cure 87.0% vs. 89.1%
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Lefamulin (Xenleta®)
Pretomanid
Approval• August, 2019
Indications• Mycobacterium tuberculosis
Approved only in combination with bedaquiline and linezolid in drug-resistant tuberculosis
Class Nitroimidazooxazine antimycobacterial drug
Mechanism of Action Blocks mycobacterial cell wall production by inhibiting mycolic acid biosynthesis
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Resistance• Mutations in M. tuberculosis genes
ddn, fgd l, fbiA, fbiB, fbiC
Products of these genes are involved in bioreductive activation of pretomanid
• Other resistance mechanism?
Not all resistant isolates have mutations in the identified M. tuberculosis genes
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Pretomanid
Dosing and Administration
Dose
• Pretomanid 200mg tablet daily
Administer with
Linezolid 1200mg daily x 26 weeks
Bedaquiline 400mg PO x 2 weeks, then 200mg 3x/week for 24 weeks
Duration may be extended beyond 6 weeks
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Pretomanid
Warnings and Precautions
• Hepatotoxicity
Discontinue if:
ALT/AST + bilirubin > 2 x ULN
ALT/AST > 8 x ULN
ALT/AST > 5 x ULN for longer than 2 weeks
• Myelosuppression
Monitor blood counts
Known adverse reaction to linezolid
• Peripheral and optic neuropathy
Neuropathy associated with linezolid
• Lactic Acidosis
Associated with linezolid
• QT Prolongation
Associated with bedaquiline use
Drug Interactions
Strong CYP3A4 inducers
Avoid co-administration
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Pretomanid
Use in specific populations
Pregnancy
Insufficient data
No associated embryofetal effects a 2 times the AUC in humans
Lactation
No human data
Detected in milk of lactating rats
Geriatric Use
Insufficient data
Pediatric Use Safety and efficacy not established
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Pretomanid
Clinical Trial Data
• Open-label study in three centers
N = 109, 51% HIV-positive
Pretomanid + bedaquiline + linezolid for 6 months
Extended to 9 months in 2 patients
89% culture negative 6-months after treatment
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
Pretomanid
Antibiotics in Development
Overview
40 antibiotics currently in development
13 in Phase 3
12 in Phase 2
15 in Phase 1
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development
Antibiotics in Development
Overview
Target Organisms
• Gram-negative ESKAPE Pathogens
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter Spp.
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development
Antibiotics in Development
Overview
Target Organisms
WHO Critical Threat Pathogens
Acinetobacter baumannii – Carbapenem resistant (CRAB)
Pseudomonas aeruginosa – Carbapenem resistant (CRPA)
Enterobacteriaceae – Carbapenem resistant, ESBL-producing
CDC Urgent threat pathogens
Acinetobacter baumannii – Carbapenem resistant (CRAB)
Candida auris
Clostridioides difficile
Enterobacteriaceae – Carbapenem resistant
Neisseria gonorrheae – Drug resistant
https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed
Antibiotics in Development
Overview
History
1 in 5 infectious disease drugs that reach human trials are approved
Current landscape
11 antibiotics in development have a novel mechanism of action or drug class
35 companies with antibiotics in clinical development
1 ranks in the top 50 pharmaceutical companies by sales
75% are pre-revenue
Too few antibiotics in development to meet anticipated need
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development
Antibiotics in Development
• Phase 3
Cefepime + enmetazobactam
Cefepime + taniborbactam
Cefilavancin
Ceftobiprole
Contezolid & contezolid acefosamil
Cespotidacin
Iclaprim
Ridinilazole
Sulbactam + durlobactam
• Sulopenem & sulopenem-etzadroxil-probenecid
• Solithromycin
• Tebipenem & tebipenem pivoxilhydrobromide
• Zolidflodacin
Antibiotics in DevelopmentCefepime + enmetazobactam
Current Status
Phase 3
Class
Benzoquinolozine fluoroquinolone
Mechanism of Action
Targets DNA gyrase preferentially over topoisomerase IV
Indication
SSTI
Hospital Acquired Bacterial Pneumoniae
Target organisms
ESKAPE pathogens
S. aureus, including MRSA
Does not cover CDC urgent or WHO critical threat pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentCefepime + enmetazobactam
Current Status
Phase 3
Class
β-lactam (cephalosporin) + β- lactamase inhibitor
Mechanism of Action
Targets Penicillin Binding Protein (PBP) and β-lactamase
Indication
Complicated intra-abdominal infections
Complicated UTI (including pyelonephritis)
Hospital Acquired Bacterial Pneumonia
Ventilator Associated Bacterial Pneumonia
Target organisms
ESKAPE Pathogens
K. pneumoniae, P. aeruginosa, Enterobacter
Possibly S. aureus
CDC urgent or WHO critical threat pathogens
ESBL producing organisms, possibly CRE
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentCefepime + taniborbactam
Current Status
Phase 3
Class
β-lactam (cephalosporin) + β- lactamase inhibitor (cyclic boronate)
Mechanism of Action
Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP)
Inhibits β-lactamase
Indication
Complicated UTI (excluding pyelonephritis)
Target organisms
ESKAPE pahtogens
K. pneumoniae, P. aeruginosa, Enterobacter spp.
Possibly S. aureus
CDC urgent or WHO critical pathogens
CRE, possibly CRPA
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentCefilavancin
Current Status
Phase 3
Class
Glycopeptide-β-lactam hybrid
Mechanism of Action
Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP)
Inhibits peptidoglycan chain elongation
Indication
Complicated UTI (excluding pyelonephritis)
Target organisms
ESKAPE pathogens
S. aureus (MRSA)
Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentCeftobiprole
Current Status
Phase 3
Class
β-lactam (cephalosporin)
Mechanism of Action
Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP)
Indication
SSTI
Community Acquired Bacterial Pneumonia
Hospital Acquired Bacterial Pneumonia
S. aureus bacteremia
Target organisms
ESKAPE pathogens
S. aureus (MRSA), K. pneumoniae, Enterobacter spp.
Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentContezolid & contezolid acefosamil
Current Status
Phase 3
Class
Oxazolidinone
Mechanism of Action
Inhibits protein synthesis
Targets bacterial 50S ribosomal subunit
Indication
SSTI
Target organisms
ESKAPE pathogens
E. faecium, S. aureus (MRSA)
Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentGespotidacin
Current Status
Phase 3
Class
Triazaacenaphthylene
Mechanism of Action
Inhibits DNA synthesis
Targets bacterial topoisomerase II at a novel A subunit site
Indication
Uncomplicated UTI
Uncomplicated urogenital gonorrhea
Target organisms
ESKAPE pathogens
S. aureus (MRSA)
CDC urgent or WHO critical pathogens
Drug-resistant N. gonorrhoeae
Possibly ESBP
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in Development
Iclaprim
Current Status
Phase 3
Class
2,4 diaminopyrimidine
Mechanism of Action
Dihydrofolate reductase inhibitor
Indication
Clostridioides difficile infection
Target organisms
Does not cover ESKAPE pathogens
CDC urgent or WHO critical pathogens
C. difficile
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in Development
Ridinilazole
Current Status
Phase 3
Class
Bis-benzimidazole
Mechanism of Action
Inhibits cell division
Reduces toxin production
Indication
Clostridioides difficile infection
Target organisms
Does not cover ESKAPE pathogens
CDC urgent or WHO critical pathogens
C. difficile
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentSulbactam + durlobactam
Current Status
Phase 3
Class
β-lactam + β-lactamase inhibitor
Mechanism of Action
Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP)
β-lactamase inhibitor
Indication
Bacteremia
Complicated UTI (including pyelonephritis)
Hospital Acquired Bacterial Pneumoniae
Ventilator Associated Bacterial Pneumoniae
Target organisms
ESKAPE pathogens
A. baumannii
CDC urgent or WHO critical pathogens
CRAB
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in Development
Sulopenem & sulopenem-etzadroxil-probenecid
Current Status
Phase 3
Class
β-lactam (carbapenem)
Mechanism of Action
Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP)
Indication
Prostatitis
Community Acquired Bacterial Pneumonia
Complicated intra-abdominal infections
Complicated UTI
Gonococcal urethritis
Pelvic inflammatory disease
Uncomplicated UTIhttps://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in Development
Sulopenem & sulopenem-etzadroxil-probenecid
Target organisms
ESKAPE pathogens
K. pneumoniae, Enterobacter spp.
CDC urgent or WHO critical pathogens
ESBL producing organisms
Drug-resistant N. gonorrhoeae
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentSolithromycin
Current Status
Phase 3
Class
Macrolide
Mechanism of Action
Inhibits bacterial protein synthesis
Targets the bacterial 50S ribosomal subunit
Indication
Community Acquired Bacterial Pneumonia
Uncomplicated urogenital gonorrhea
Target organisms
Does not cover ESKAPE pathogens
CDC urgent or WHO critical pathogens
Drug-resistant N. gonorrhoeae
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in DevelopmentTebipenem & tebipenem pivoxil hydrobromide
Current Status
Phase 3
Approved for use in Japan (Orapenem®) for pneumonia, otitis media, sinusitis
Class
Carbapenem
Mechanism of Action
Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP)
Indication
Complicated UTI (including pyelonephritis)
Community Acquired Bacterial Pneumonia
Diabetic foot infection
Target organisms
ESKAPE pathogens
K. pneumoniae
Possibly A. baumannii, P. aeruginosa
CDC urgent or WHO critical pathogens
ESBL producing organisms
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Antibiotics in Development
Zoliflodacin
Current Status
Phase 3
Class
Spiropyrimidinetrione
Mechanism of Action
Inhibits bacterial DNA synthesis
Targets bacterial type II topoisomerase
Indication
Uncomplicated gonorrhea
Target organisms
ESKAPE pathogens
S. aureus
CDC urgent or WHO critical pathogens
Drug-resistant N. gonorrhoeae
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
Assessment Questions1. Which of the following statements regarding new antibacterial agents is
true?A. Most are FDA approved to treat a broad range of infections
B. Recently approved antibiotics are likely to become first-line agents
C. Many have a novel mechanism of action
D. Most are reserved for infections caused by organisms that are resistant to existing antibiotics
2. The majority of antibiotics currently in development target which pathogen(s)?
A. Gram-positive organisms
B. Gram-negative ESKAPE pathogens
C. Drug-resistant Neisseria gonorrheae
D. Drug-resistant Clostridioides difficile
References1. Aemcolo [package insert]. San Diego, Ca: Aries Pharmaceuticals, Inc; 2018.
2. Antibiotics Currently in Global Clinical development. Data Visualization April 15, 2020. PEW website. Available at: Antibiotics Currently in Clinical Development | The Pew Charitable Trusts (pewtrusts.org). Accessed February 28, 2021.
3. Clinical study of S-649266 for the treatment of nosocomial pneumonia caused by gram-negative pathogens (APEKS-NP). Available at: https://clinicaltrials.gov/ct2/show/NCT03032380. Accessed Jan. 20, 2020.
4. Fetroja [package insert]. Florham Park, NJ: Shionogi Inc; 2019.
5. Food and Drug Administration. FDA Antibacterial Susceptibility Test Interpretive Criteria. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. Accessed Feb. 10, 2020.
6. Hagwat SS, et al. Levonadifloxacin, a novel broad-spectrum Anti-MRSA benzoquinolizine quinolone agent: review of current evidence. Drug Des Devel Ther 2019, 13: 4351-4365.
7. Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother 2017;62:e01454-17.
8. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2016;60:7396-7401.
9. Katsube T, Echols R, Wajima T. Pharmacokinetic and pharmacodynamic profiles of cefiderocol, a novel siderophore cephalosporin. Clin Infect Dis 2019;69(Suppl7):S552-S558.
References10. Mulani S, Kamble EE, Kumkar SN, Tawre SM, Pardesi KR. Emerging Strategies to Combat ESKAPE
Pathogens in the Era of Antimicrobial Resistance: A Review. Front Microbiol 2019;10:539.
11. Nuzyra [package insert]. Boston, MA: Paratek pharmaceuticals, Inc; 2018.
12. Nuzyra website. Available at:https://www.nuzyra.com/hcp/. Accessed February 26, 2021.
13. Pretomanid [package insert]. South San Francisco, CA: Achaogen, Inc; 2018.
14. Seysara [package insert]. Madison, NJ: Allergan USA, Inc; 2018.
15. Moore AY, Charles JE, Moore S. Sarecycline: a narrow spectrum tetracycline for the treatment of moderate-to-severe acne vulgaris. Future Microbiology 2019;14;4. Available at: https://www.futuremedicine.com/doi/10.2217/fmb-2019-0199. Accessed February 28, 2021.
16. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: A phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319-1328.
17. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin Infect Dis 2019;69(Suppl 7):S538-S543.
18. Tracking the Global Pipeline of Antibiotics in Development, April 2020. PEW website. Available at: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development. Accessed February 28, 2020.
References
18. WHO publishes list of bacteria for which new antibiotics are urgently needed. 2017. World Health Organization website. Available at: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. Accessed February 10, 2021.
19. Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important gram-negative bacteria. Clin Infect Dis 2019;69(Suppl7):S544-S551.
20. Xenleta [package insert]. Nabriva Therapeutics US; 2019.
21. Xerava [package insert]. Watertown, MA: Tetraphase Pharmaceuticals, Inc; 2018.
22. Xerava™ website. Available at: https://www.xerava.com/. Accessed February 26, 2021.
23. Zemdri [package insert]. South San Francisco, CA: Achaogen, Inc; 2018.
24. Zemdri website. Available at: https://zemdri.com/. Accessed February 26, 2021.